norgestomet and Breast-Neoplasms

To provide insight into potential mechanisms contributing to the various biological responses of cattle to treatment with progesterone, norgestomet, and melengestrol acetate (MGA), MCF-7 cells were utilized to determine the relative binding affinity of the progesterone receptor for MGA, norgestomet, progesterone, and a progesterone agonist (R5020), and to determine if progesterone, MGA, or norgestomet have estrogenic and/or anti-estrogenic activities. The progesterone receptor had greater affinity (P<0.05) for MGA, R5020, and norgestomet than for progesterone; and the affinity for norgestomet exceeded (P<0.05) that of MGA and R5020. Estrogen stimulates proliferation of MCF-7 cells; therefore these cells have been utilized as a bioassay to detect estrogenic and anti-estrogenic activity. Progesterone (10(-11) to 10(-5)M) did not promote cellular proliferation. However, MGA (10(-8), 10(-7), and 10(-6)M) increased (P<0.05) cell proliferation compared to the control group (10(-11) to 10(-9) and 10(-5)M MGA did not stimulate cell proliferation), and MGA-induced cell proliferation (10(-8)M) was reduced (P=0.095) by an estradiol antagonist (ICI 182,780; ICI). Cellular proliferation increased (P<0.05) with norgestomet (10(-5)M) compared to the control group (10(-11) to 10(-6)M norgestomet did not stimulate cell proliferation) and the increased proliferation was decreased (P<0.05) by ICI. Neither progesterone nor MGA demonstrated anti-estrogenic activity. Norgestomet (10(-10) to 10(-6)M) did reduce (P<0.05) maximal estrogen-stimulated cell proliferation, but not to basal levels. In summary, the affinities of the progesterone receptor for norgestomet, MGA, and progesterone are consistent with their effective dose to inhibit ovulation in vivo, but their progestin and their estrogenic/anti-estrogenic activities cannot fully explain why progesterone and norgestomet are more capable of reprogramming the reproductive axis in anestrous postpartum cows compared to MGA.

Topics: Animals; Binding, Competitive; Breast Neoplasms; Cattle; Cell Line, Tumor; Cell Proliferation; Estradiol; Estrogen Receptor Modulators; Estrogens; Female; Fulvestrant; Hormone Antagonists; Humans; Inhibitory Concentration 50; Melengestrol Acetate; Pregnenediones; Progesterone; Progestins; Promegestone; Receptors, Progesterone

Norgestomet is the progestational component present in Syncro-Mate-B, which is used to synchronize estrus in cattle. In post-partum cows, luteal phases anticipated to be short following first ovulation are of normal length when cows are pretreated with norgestomet. Because Syncro-Mate-B is used experimentally as a progestogen to affect uterine function, these studies were conducted to investigate how norgestomet acts at the level of the uterus. Receptor binding assays and a sensitive estrogen bioassay in tissue culture were used to address the possibility that some effects of norgestomet might be mediated through interaction of this compound with steroid hormone receptors other than the progesterone receptor (rP). The source of receptors was high-speed cytosol, prepared from bovine uterine endometrium, which was obtained from cyclic cows. Results of single-point and complete competition analyses comparing norgestomet and progesterone indicated that norgestomet competed even more effectively than did progesterone for specific binding of [3H]progesterone to rP. Results of similar studies, which compared the abilities of norgestomet and diethylstilbestrol to compete with [3H]estradiol for binding by uterine endometrial estrogen receptors (rE), provided no evidence for norgestomet competitive binding to rE. In MCF-7 breast cancer cell bioassays, norgestomet showed weak estrogenic activity, but only at concentrations greater than 1 micromolar. Finally, norgestomet did not compete with [3H]triamcinolone acetonide when present in an 100-fold excess, and only competed with [3H]dexamethasone for binding by endometrial glucocorticoid receptors (rG) when present in the micromolar range. We conclude that, at the concentrations used in synchronizing estrus, norgestomet interacts with bovine endometrium as a progestogen and that its biological actions occur through binding of this compound to rP present in target tissues.

Topics: Animals; Binding, Competitive; Breast Neoplasms; Cattle; Cells, Cultured; Dexamethasone; Endometrium; Estradiol; Estrus Synchronization; Female; Humans; Pregnenediones; Progesterone; Progesterone Congeners; Receptors, Estrogen; Receptors, Progesterone; Receptors, Steroid; Tamoxifen; Triamcinolone Acetonide; Tumor Cells, Cultured